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The Cognitive Impact of Soluble Fibrillogenic Aβ Oligomers In Prodromal Dementia
HEALTHY ELDERLY
ALZHEIMER’S DISEASE
Dr Kevin Ong, MBBS DPMSA DMedSc FRACPProf Michael Woodward, AM MBBS MD FRACPAIBL Research Group
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Disclosures
• Michael Woodward has worked on AD drug trials funded by pharmaceutical companies including AbbiVie, Astra Zeneca, AZ therapies, Biogen, Buck, Eisai, Janssen, Lilly, Lundbeck, Merck/MSD, Novartis, Pfizer, Roche, Servier, Takeda, Tau Rx, vTv Therapeutics and Zinfandel. He has also received honoraria for consultancies or presentations at meetings organized by CogRx, Lundbeck, Merk Sharp & Dohme, Novartis, Nestle and Nutricia.
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Disclosures
• Kevin Ong wished he had something to disclose.
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Sperling et al., Alzheimer’s & Dementia, 2011.
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O’Brien & Wong, Annu Rev Neurosci, 2011.
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Meta-analysis by Jansen et al., JAMA, 2015.
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Tracking The Progression of Alzheimer Changes In VivoMechanism
Upstream events (e.g.,Aβ dimers, oligomers)
Biomarker
Aβ aggregation; deposition as cerebral diffuse plaques
Amyloid plaques exert synaptic/neuronal damage
Substantial synaptic/neuronal damage
Note: Other processes (e.g., inflammation; oxidative stress; vascular insufficiency) likely contribute
Prodromal AD
AD dem
entia
? ? ?Aβ Imaging;
↓ CSF Aβ42 levels
↓ brain metabolism (FDG); Brain volume loss (MRI)
Dementia severity marked by increasing volume loss, and ↑ CSF tau&ptau levels
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1. CSFAβ levels are not in equilibrium with cerebral Aβplaque burden detected by Amyloid PET.
2. We can detect soluble Aβ oligomers in vivo. But are they fibrillogenic?
– Increased CSF Aβ42:Aβ40 ratio is associated with FTD, not AD?! • Vitali 2004; Pijnenburg 2007; Bernardi 2009; Dermaut 2004.
Tracking Aβ Oligomers Upstream
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Tracking Fibrillogenic Aβ• We can assume the presence of fibrillogenic Aβ
oligomers if there is increased tracer uptake on serial amyloid PET
Before After some time
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Methods• 45 participants (age 73±6.6) referred from Memory Disorders specialists –
• At least one cognitive test score < -1.5 SD (Petersen’s criteria). • Clinical diagnosis of MCI, MMSE 24-30.
• Neuropsychological tests – Logical Memory, CVLT, Rey Figure, etc.
• MRI: 3D T1-MPRAGE, T2, FLARE.
• PET: 90-110 min after 300 MBq of Florbetaben (FBB).• Image analysis:
• Florbetaben (FBB) PET - SUVR using the cerebellar cortex as reference region. • MRI – Hippocampal Volume determined by NeuroQuant®; WMH determined by manual
segmentation with MRIcro software.• Statistical analysis:
• Linear regression.• Adjusted for age, gender, and years of education.
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Methods• MRI and Florbetaben (FBB) PET repeated at 12 and
24 months from baseline.– FBB PET (n=74) 98% sensitivity, 89% specificity for
confirming significant plaque load in autopsy studies. • Clinical assessment annually for 2 years then again at
4 years.
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Neo
corti
cal S
UVR
90-1
10
HC1.29±0.2(n=15)
2.6
2.0
1.5
1.0
2.4
2.2
1.8
1.2
1.4
AD2.03±0.3(n=15)
MCI1.46±0.4(n=45)
Amyloid Imaging18F-Florbetaben
20%
100%
53%,n=24
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RelationshipsAβ
HV WMH
EM NM
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RelationshipsAβ
HV WMH
EM NM
r=-0.51, p<0.01
r=+0.60, p<0.05 Spearman’s ρ=-0.48, p<0.001
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RelationshipsAβ
HV WMH
EM NM
r=-0.49, p<0.05,
corr HVr=+0.33, p<0.05,
corr Aβ (SUVR)
Both Aβ and hippocampal atrophy may have a direct and independentrelationship with memory impairment in MCI.
Spearman’s ρ=-0.48, p<0.001
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Hippocampal atrophy
Aβ burden
Memory loss
r=-0.44, p<0.01
r=0.26, ns
Baseline (excluding 9 drop outs)
ns
n=36
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Hippocampal atrophy
Aβ burden
Memory loss
r=-0.26, ns
r=0.36, p<0.05
r=0.32, p=0.06
n=36
After 2 years
Hippocampal atrophy overtakes Aβ in driving memory impairment, and increasingly mediates this relationship, as disease progresses.
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Changes in FBB SUVR over 2 years
• SUVR increased by 2.2% (0.037) per year in those with high Aβ at baseline, p<0.01
• We assume the presence of fibrillogenic Aβ oligomers if there is increased tracer uptake on serial amyloid PET.
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Early progressive memory loss • Possibly driven by soluble fibrillogenic Aβ oligomers
just upstream to deposited Aβ plaques.
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•Accuracy of FBB PET in predicting MCI conversion to AD over 2 years was 82.8%
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POST HOC ANALYSIS:
1. Age. 2. Years of education3. Gender. 4. High cerebral amyloid load
(FBB+). 5. Hippocampal atrophy.
6. Poor EM. 7. Poor nonmemory-related
cognitive function (NM). 8. Clinical dementia rating sum of
boxes (CDR SOB). 9. White matter hyperintensity. 10.Number of cardiovascular risk
factors.
To compare the risk factors (co-variates) below for MCI progression to AD
11. Increase in FBB tracer uptake (≡ presence of fibrillogenic Aβoligomers)
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• Cox regression.• Compare (& simultaneously correct) effects of several risk
factors on unwanted events occurring.
POST HOC ANALYSIS:
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Increased tracer uptake• Did not predict Alzheimer’s disease.
– Two & four years follow-up: HR ns!• Predicted all cause dementia.
– Two years follow-up: HR 4.8, p=0.027.– Four years follow-up: HR 6.9. p=0.010.
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Summary1. Early memory decline and hippocampal atrophy may be
caused by soluble fibrillogenic Aβ oligomers upstream to Aβ plaques.
2. Fibrillogenic Aβ oligomers upstream to Aβ plaques are non-specific for AD dementia!
• Aβ plaque accumulation may be the cause of AD (Amyloid Cascade Hypothesis).
• Is Aβ plaque accumulation in AD a means to buffer the effects of Aβ-amyloidosis in non-AD?Clinically, non-AD dementia sufferers generally experience a more malignant
course compared to those with AD!
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The Ong-Woodward Hypothesis1
Cognitive function
Time/years
Normal ageing
Accumulation of Aβ into dense plaques delays decline (Alzheimer’s disease)
Cerebral β-amyloidosis
Accumulation of Aβ into sparse plaques (non-AD dementias)
1. Ong and Woodward. ANZJP, in press.
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Finding the right targets
Aβ monomers(non-toxic, beneficial functions possible)
APP
Aβ oligomers(NEUROTOXIC)
Aβ plaques(Buffer, relatively inert)
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Finding the right targets
Aβ monomers(non-toxic, beneficial functions possible)
APP
Aβ oligomers(NEUROTOXIC)
Aβ plaques(Buffer, relatively inert)
-
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Finding the right targets
Aβ monomers(non-toxic, beneficial functions possible)
APP
Aβ oligomers(NEUROTOXIC)
Aβ plaques(Buffer, relatively inert)
-
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Finding the right targets
Aβ monomers(non-toxic, beneficial functions possible)
APP
Aβ oligomers(NEUROTOXIC)
Aβ plaques(Buffer, relatively inert)
--
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Finding the right targets
Aβ monomers(non-toxic, beneficial functions possible)
APP
Aβ oligomers(NEUROTOXIC)
Aβ plaques(Buffer, relatively inert)
--
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Finding the right targets
Aβ monomers(non-toxic, beneficial functions possible)
APP
Aβ oligomers(NEUROTOXIC)
Aβ plaques(Buffer, relatively inert)
--
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Finding the right targets
Aβ monomers(non-toxic, beneficial functions possible)
APP
Aβ oligomers(NEUROTOXIC)
Aβ plaques(Buffer, relatively inert)
--
Verubecestat (BACE-1 inhibitor) FAIL, NEJM 2019
-
Aducanumab, Solanezumab and Bapineuzumab, FAIL, FAIL FAIL
-- +
ϒ-Secretase inhibitors, FAIL -
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The Woodward-Ong HypothesisAD drugs are more likely to work if they:
1. Specifically reduce soluble Aβ oligomers levels cerebrally,
AND
2. Enhance Aβ plaque formation and stability.
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Finding the right targets
Aβ monomers(non-toxic, beneficial functions possible)
APP
Aβ oligomers(NEUROTOXIC)
Aβ plaques(Buffer, relatively inert)
--
“W-O” Drugs
- + -
+
-
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Limitations• Single centre.• Limited data.• Serial scanning increases noise.
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AcknowledgementsAustin Health (Melbourne):• Christopher Rowe• Victor Villemagne• Kerryn Pike• Alex Bahar-Fuchs• Fiona Lamb• Narelle Langdon• Colin Masters• Gael Chetelat
Bayer/Piramal employees:•Ana Catafau •Andrew Stephens•Ludger Dinkelborg•Cornelia Reininger•Barbara Putz •Beate Rohde
Supported in part by Bayer-Schering Pharma, Austin Health Medical Research Foundation, NHRMC grant 509166
Participants and their families